The renin-angiotensin system has long been suspected of being involved in the pathogenesis or maintenance of hypertensive diseases. A firm correlation has been found for renovascular hypertension, where excess renin release from the kidney has been documented, and for oral contraceptive induced hypertension where the correlation is with excess angiotensinogen. However, attempts to document the role of the renin-angiotensin system in essential hypertension have not been successful. Classification on the basis of plasma renin levels has been facilitated the design of therapy for essential hypertensives, however it has not contributed to an understanding of the etiology of the disease. In addition, the renin-angiotensin system has been implicated in other diseases such as preeclampsia, stroke, hepatorenal syndrome and sarcoidosis. The one component of the system frequently found to correlate with hypertension is elevated levels of angiotensinogen. This serum glycoprotein, released from the liver, is the precursor of angiotensin. Our findings of polymorphism of human angiotensinogen and our demonstration that the protein is present in extravascular rabbit brain tissue provides a new concept to the pathological involvement of the renin-angiotensin system. We propose that an abnormality in angiotensinogen polymorphism or in the rate of the renin-angiotensinogen reaction may underlie the pathological contribution of the renin-angiotensin system to several disease states, including essential hypertension. We will examine this hypothesis by characterizing the molecular basis and the pathophysiological importance of the polymorphism and document levels of the forms of the protein in both clinical and experimental animal studies. Further, we will examine both the rate of passage of angiotensinogen into the CNS and determinants of the rate of renin-angiotensinogen reaction. Lastly, we will evaluate the role of the renin-angiotensin system in cerebral vascular hemorrhage and the contribution of intra-cranial generation of angiotensin to enhanced tissue damage in the early stages of the hemorrhage.